title: Putative bioactive motif of tritrpticin revealed by an antibody with biological receptor-like properties.
abstract: Antimicrobial peptides represent one of the most promising future strategies for combating infections and microbial drug resistance. Tritrpticin is a 13mer tryptophan-rich cationic antimicrobial peptide with a broad spectrum of activity whose application in antimicrobial therapy has been hampered by ambiguity about its biological target and consequently the molecular interactions necessary for its antimicrobial activity. The present study provides clues about the mechanism of action of tritripticin by using a unique monoclonal antibody (mAb) as a 'physiological' structural scaffold. A pool of mAbs were generated against tritrpticin and based on its high affinity and ability to bind tritrpticin analogs, mAb 6C6D7 was selected and characterized further. In a screening of phage displayed random peptides, this antibody was able to identify a novel antimicrobial peptide with low sequence homology to tritrpticin, suggesting that the mAb possessed the physico-chemical characteristics mimicking the natural receptor. Subsequently, thermodynamics and molecular modeling identified a core group of hydrophobic residues in tritrpticin arranged in a distorted's' shaped conformation as critical for antibody binding. Comparison of the mAb induced conformation with the micelle bound structure of tritrpticin reveals how a common motif may be able to interact with multiple classes of biomolecules thus extending the target range of this innate immune peptide. Based on the concurrence between thermodynamic and structural data our results reveal a template that can be used to design novel antimicrobial pharmacophores while simultaneously demonstrating at a more fundamental level the potential of mAbs to act as receptor surrogates.
authors.affiliation: National Institute of Immunology, New Delhi, India.
authors.forename: Raghava
authors.initials: R
authors.lastname: Sharma
authors.forename: Suvendu
authors.initials: S
authors.lastname: Lomash
authors.forename: Dinakar M
authors.initials: DM
authors.lastname: Salunke
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism*; D023181:Antimicrobial Cationic Peptides / Q000378:metabolism*; D005260:Female; D051379:Mice; D008807:Mice, Inbred BALB C; D008823:Micelles; D009842:Oligopeptides / Q000378:metabolism*; D013816:Thermodynamics
chemical_list: D000911:Antibodies, Monoclonal; D023181:Antimicrobial Cationic Peptides; D008823:Micelles; D009842:Oligopeptides; C402895:tritrpticin